The direct relationship between hyperglycemia and nonenzymatic glycation, the condensation between free glucose and reactive protein amino groups that is accelerated in diabetes, has implicated this reaction in the development of diabetic complications. Experimental studies have shown that albumin modified by Amadori glucose adducts has distinct biologic effects that unmodified albumin does not possess. Renal glomeruli isolated from normal rats exhibit preferential uptake of glycated albumin relative to nonglycated albumin, which is accompanied by an increase in cell hydrogen peroxide production, and this abnormality can be duplicated in glomerular cells from normal rats by injecting glycated albumin and raising its circulating concentration (Daniels et al, J Am Soc Nephrol 4:791A, 1993). Normal rats transfused with glycated serum proteins containing Amadori products of the glycation reaction in concentrations similar to those found in streptozotocin diabetic rats manifest hyperfiltration, a functional abnormality observed early in the development of diabetic nephropathy (Sabbatini et al, Kidney Int 42:875, 1992). Human sera containing diabetic concentrations of glycated albumin stimulate mesangial cell synthesis and gene expression of type IV collagen, the principal constituent of the expanded extracellular matrix observed in the diabetic renal glomerulus (Cohen and Ziyadeh, Kidney Int 45:475, 1994; Ziyadeh and Cohen, Mol Cell Biochem 125:19, 1993; Cohen et al, Mol Cell Biochem 151:61, 1995). The glycated albumin-induced in vitro effects on mesangial cell biology mimic the changes that characterize human diabetic nephropathy, are likely mediated by ligand-receptor systems that recognize the glucose-modified epitope in glycated albumin, and can be prevented by molecules capable of reacting with N-deoxyfructosyllysine in glycated albumin (Wu and Cohen, Biochem Biophys Res Comm 207:521, 1995). One such molecule is a murine monoclonal antibody, A717, which specifically binds to epitopes containing Amadori glucose adducts that are present on glycated albumin but are not present on nonglycated albumin, and which is disclosed in U.S. Pat. No. 5,223,392 and U.S. Pat. No. 5,518,720. Administration of the murine A717 to diabetic mice prevents the changes in renal structure and function observed in diabetic control mice; namely, increased urine protein excretion, overproduction of matrix macromolecules, and accumulation of glomerular extracellular matrix (Cohen et al Kidney Int 45:1673, 1994; Cohen et al, J Clin Invest 95:2338, 1995). These properties of murine monoclonal antibodies in a murine model indicate that humanized antibodies with the same specificity for neutralizing the biologic effects of increased glycated albumin would be beneficial in the treatment of human diabetic nephropathy.
Monoclonal antibodies have emerged as therapeutic modalities for various pathological conditions including malignant, cardiovascular and autoimmune disease. However, clinical trials with murine monoclonal antibodies have indicated that administration of murine IgG elicits a brisk human humoral anti-murine immunoglobulin (HAMA) response that can reduce the circulating half-life of the antibody and produce allergic reactions. Almost all of the murine monoclonal antibodies used clinically have provoked HAMA responses, including HAMA against the framework, the isotype and the idiotype of the murine IgG antibodies. Even though severe side-effects are rare in patients with HAMA following treatment with antibody, most investigators take the position that if monoclonal antibodies are to be used therapeutically, reliable methods for avoiding an immune response must be devised. Genetically engineered antibodies are deemed to address these concerns. They can be constructed to have specific effector functions derived from the structures of different classes and isotypes, and new antibody variants with desired properties and minimal side-effects can be created in vitro.
It would therefore be desirable to create a genetically engineered monoclonal antibody that retains the binding specificities of the murine monoclonal A717 but possesses human antibody structural features at the level of immunoglobulin gene sequences.